Helicobacter pylori (H pylori) infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. After more than 20 years of experience in H pylori treatment, in my opinion, the ideal regimen to treat this infection is still to be found. Currently, apart from having to know first-line eradication regimens well, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a "rescue" treatment depends on which treatment is used initially. If a clarithromycin-based regimen was used initially, a subsequent metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin-based combination would be a third "rescue" option. Alternatively, it has recently been suggested that levofloxacin-based rescue therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, a quadruple regimen may be reserved as a third-line rescue option. Finally, rifabutin-based rescue therapy constitutes an encouraging empirical fourth-line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H pylori eradication can finally be achieved in almost all patients if several rescue therapies are consecutively given. Therefore, the attitude in H pylori eradication therapy failure, even after two or more unsuccessful attempts, should be to fight and not to surrender.